1. Acquire an appreciation for the fact that virtually all disease have a genetic component (p.336)
All disease have a genetic component. Either genetics directly causes a disease or provides susceptibility for the disease.
2. Differentiate among the four types of genetic disease (p.338)
Single Gene (Mendelian)
Numerous, but individually rare. Clear pattern of inheritance in most cases and high risk for relatives with the highest risk for first degree relativees.
Multifactorial
Common disorders. No clear pattern of inheritance with low or moderate risk for relatives.
Chromosomal
Not always a clear pattern of inheritance. Risk to relatives dependent on type of abnormality and is a common cause of pregnancy loss.
Somatic Mutation
Aquired mutations resulting in neoplasia
3. Acquire an appreciation for the impact of genetic disease in prenatal, perinatal, and postnatal settings. (p.338)
Different genetic diseases tend to be detected at different times in life. Most chromosomal disease are detected prenatally with very few being undetected after birth. However, multifactorial defects tend to remain undetected until well into adulthood. Single gene (mendelian) defects are often detected perinatally, escaping detection prenatally and rarely remaining undetected until adulthood.
4. Review the types and frequencies of genetic disease in the population (p.339)
Type
Frequency by 25 years
Frequency after 25 years
Lifetime Frequency
Chromosomal Disorders
1.8 / 1,000
2 / 1,000
3.8 / 1,000
Single Gene Disorders
3.6 / 1,000
16.4 / 1,000
20 / 1,000
Multifactorial (Part-Genetic) Disorders
46.4 / 1,000
600 / 1,000
646.4 / 1,000
Somatic Cell (Cumulative) Genetic Disorders
--
240 / 1,000
240 / 1,000
5. Differentiate between genetic determinism and genetic susceptibility (p.340)
Genetic determinism refers to genetic defects that determine a disease while genetic susceptibility refers to genetic defects and confer susceptibiity to getting a disease.
That is, in genetic determinism, a woman heterozygous for an X-linked genetic disorder has a 50% risk of passing on the disease to her male children; if the male children do inherit the genetic defect, they will develop the disease. However, if the genetic disorder confers genetic susceptibility instead, then her male descendents who inherit this risk are more susceptible to getting the disease but not guarenteed to develop the disease.
6. Consider both the myths and realities of the Human Genome Project (p.343)
Myths
We will know the cause of all disease. Disease can be predicted and prevented. Gene therapy can be the silver bullet.
Realities
We will know all the genes. Presymtomatic testing works, if you have a treatment for the disease. Differential diagnosis/prognosis/management is possible. Genetic variation can be used as a discriminator.
7. Describe the potential benefits of the Human Genome Project on Health Care (p.343)
Benefits of the human genome project incldue new patients, improved diagnositic efficiency (genomic triage), intellectual property, translational research, single nucleotide polymorphism profiles for the prediction of disease susceptibility and pharmacogenetics.
8. Review the basic principles of Molecular Pathology including the mechanisms of DNA mutation and possible outcomes associated with DNA damage (p.346)
Chemical insult, DNA modification, or physical insult can result in altered genomic DNA. Chemical insult includes N-nitroso compounds, polycyclic aromatic hydrocarbons, and crosslinking agents. DNA modification can occur via transposons, unequal crossing over, or segmental genome duplication. Physical insult can include ionizing radiation and ultraviolet radiation. Damaged DNA can be corrected by DNA repair mechanisms (nucleotide excision repair, enzymatic reversal). However, deficiencies in DNA repair can result in the generation of stable DNA mutations.
9. Describe the various types of DNA damage (p.345)
Types of Genetic Mutations
Aneuploidy - alteration in the number of copies of genome
Chromosomal abnormalities - duplicated chromosomes, breakages and incorrect reattachment
Gene amplification - increase in gene copy number
Gene mutation - point mutation, insertional mutation, deletions
Molecular Collection of Gene Mutations
Point mutations - alternation of individual nucleotides in a gene sequence. Missense mutations may or may not change the coded amino acid. Nonsense mutations produces a stop codon where an amino acid should be.
Insertional mutations - additon of nucleotides that disrupt the coding sequence of a gene. Can result in a frameshift that alters the reading frame downstream of the mutation or in-frame mutation that results in the loss of amino acids within the frameshifted region but recovery of reading frame afterwards.
Deletion - Loss of nucleotides
Splicing mutation - errors in splicing resulting in formation of exonic splice sites or cryptic slplice sites (i.e., a splice site where there shouldn't be one) or exon skipping (loss of a splice site)
10. Review the advantages and limitations of molecular genetic testing as well as present and future molecular diagnostic techniques including DNA microarray technology (p.353)
Advantages
Unambigous determination of the presence or absence of a mutation
Diagnosis can be made well in advance of symptoms
Can distinguish between disorders of similar phenotypes
Identifying specific mutation may be prognostically significant
DNA from peripheral blood allows for more non-invasive procedures
Chroionic villi or amniotic fluid cells can be used for prenatal testing
Limitations
Heterogeneity of genetic changes that underly inherited disorders (allelic heterogeneity)
State-of-the-art diagnostics and curative therapies lag behind gene testing
Insurance and employment discrimination
Some molecular tests are costly and not covered by insurance (or patient doesn't want the insurer to know they are being tested)
11. Acquire an appreciation for the importance of genomic medicine in the primary care setting. (p.357)
Physicans armed with genomic medicine in the primary care setting will be able to move from intense, crisis-driven intervention to preventative medicine by utilizing genomic tests to identify individual susceptibility to common disorders such as heart disease, diabetes, and cancer. Identification of a genomic profile consistent with an elevated risk would lead to primary prevention (diet and exercise) and secondary prevention (early detection or pharmacologic intervention). Screening will be based on importance of a given condition to public health, availability of a highly sensitive genomic assay, availability of pre-symptomatic treatment, and cost considerations
12. Describe the barriers to provision of genetic services as they exist in medicine today. (p.358)
Barriers
Lack of genetic knowledge
Lack of detailed/updated family history
Lack of referral guidelines or tools to facilitate their use
Lack of confidence for delivering genetic services, assessing, and managing risk
High cost of services
Funding resources
Insurance problems
Perception of limited or no benefit from genetic services
Skepticism about validity/utility of genetic testing
No information on how to manage moderate risk for genetics-related disease
Objectives
1. Acquire an appreciation for the fact that virtually all disease have a genetic component (p.336)
All disease have a genetic component. Either genetics directly causes a disease or provides susceptibility for the disease.
2. Differentiate among the four types of genetic disease (p.338)
Single Gene (Mendelian)
Numerous, but individually rare. Clear pattern of inheritance in most cases and high risk for relatives with the highest risk for first degree relativees.
Multifactorial
Common disorders. No clear pattern of inheritance with low or moderate risk for relatives.
Chromosomal
Not always a clear pattern of inheritance. Risk to relatives dependent on type of abnormality and is a common cause of pregnancy loss.
Somatic Mutation
Aquired mutations resulting in neoplasia
3. Acquire an appreciation for the impact of genetic disease in prenatal, perinatal, and postnatal settings. (p.338)
Different genetic diseases tend to be detected at different times in life. Most chromosomal disease are detected prenatally with very few being undetected after birth. However, multifactorial defects tend to remain undetected until well into adulthood. Single gene (mendelian) defects are often detected perinatally, escaping detection prenatally and rarely remaining undetected until adulthood.
4. Review the types and frequencies of genetic disease in the population (p.339)
5. Differentiate between genetic determinism and genetic susceptibility (p.340)
Genetic determinism refers to genetic defects that determine a disease while genetic susceptibility refers to genetic defects and confer susceptibiity to getting a disease.
That is, in genetic determinism, a woman heterozygous for an X-linked genetic disorder has a 50% risk of passing on the disease to her male children; if the male children do inherit the genetic defect, they will develop the disease. However, if the genetic disorder confers genetic susceptibility instead, then her male descendents who inherit this risk are more susceptible to getting the disease but not guarenteed to develop the disease.
6. Consider both the myths and realities of the Human Genome Project (p.343)
Myths
We will know the cause of all disease. Disease can be predicted and prevented. Gene therapy can be the silver bullet.
Realities
We will know all the genes. Presymtomatic testing works, if you have a treatment for the disease. Differential diagnosis/prognosis/management is possible. Genetic variation can be used as a discriminator.
7. Describe the potential benefits of the Human Genome Project on Health Care (p.343)
Benefits of the human genome project incldue new patients, improved diagnositic efficiency (genomic triage), intellectual property, translational research, single nucleotide polymorphism profiles for the prediction of disease susceptibility and pharmacogenetics.
8. Review the basic principles of Molecular Pathology including the mechanisms of DNA mutation and possible outcomes associated with DNA damage (p.346)
Chemical insult, DNA modification, or physical insult can result in altered genomic DNA. Chemical insult includes N-nitroso compounds, polycyclic aromatic hydrocarbons, and crosslinking agents. DNA modification can occur via transposons, unequal crossing over, or segmental genome duplication. Physical insult can include ionizing radiation and ultraviolet radiation. Damaged DNA can be corrected by DNA repair mechanisms (nucleotide excision repair, enzymatic reversal). However, deficiencies in DNA repair can result in the generation of stable DNA mutations.
9. Describe the various types of DNA damage (p.345)
Types of Genetic Mutations
Aneuploidy - alteration in the number of copies of genome
Chromosomal abnormalities - duplicated chromosomes, breakages and incorrect reattachment
Gene amplification - increase in gene copy number
Gene mutation - point mutation, insertional mutation, deletions
Molecular Collection of Gene Mutations
Point mutations - alternation of individual nucleotides in a gene sequence. Missense mutations may or may not change the coded amino acid. Nonsense mutations produces a stop codon where an amino acid should be.
Insertional mutations - additon of nucleotides that disrupt the coding sequence of a gene. Can result in a frameshift that alters the reading frame downstream of the mutation or in-frame mutation that results in the loss of amino acids within the frameshifted region but recovery of reading frame afterwards.
Deletion - Loss of nucleotides
Splicing mutation - errors in splicing resulting in formation of exonic splice sites or cryptic slplice sites (i.e., a splice site where there shouldn't be one) or exon skipping (loss of a splice site)
10. Review the advantages and limitations of molecular genetic testing as well as present and future molecular diagnostic techniques including DNA microarray technology (p.353)
Advantages
Limitations
11. Acquire an appreciation for the importance of genomic medicine in the primary care setting. (p.357)
Physicans armed with genomic medicine in the primary care setting will be able to move from intense, crisis-driven intervention to preventative medicine by utilizing genomic tests to identify individual susceptibility to common disorders such as heart disease, diabetes, and cancer. Identification of a genomic profile consistent with an elevated risk would lead to primary prevention (diet and exercise) and secondary prevention (early detection or pharmacologic intervention). Screening will be based on importance of a given condition to public health, availability of a highly sensitive genomic assay, availability of pre-symptomatic treatment, and cost considerations
12. Describe the barriers to provision of genetic services as they exist in medicine today. (p.358)
Barriers